This invention relates to compositions and processes that provide sub-micron and micron size stable particles of water-insoluble or poorly soluble drugs or other industrially useful insoluble compounds. The compositions of this invention include combinations of natural or synthetic phospholipids, a charged surface modifier such as a highly purified charged phospholipid, and a block copolymer coated or adhered onto the surfaces of the water insoluble-compound particles. The combination of charged surface modifier and block copolymer allows the formation and stabilization of the sub-micron and micron size compound particles. The particles are stabilized by the charged surface modifier which provides electrostatic stabilization, and by the block copolymer which provides steric stabilization. The combination of charged surface modifier and block copolymer stabilize these particles with respect to particle growth, aggregation or flocculation.
There is a critical need in the pharmaceutical and other biological based industries to formulate water-insoluble or poorly soluble substances into formulations for oral, injectable, inhalation, ophthalmic, and other routes of delivery. Water insoluble substances are those having poor solubility in water, that is  less than 5 mg/ml at physiological pH (6.5-7.4). Preferably their water solubility is  less than 1 mg/ml, and more preferably  less than 0.1 mg/ml. Water-insoluble or poorly soluble substances as used herein include water-insoluble or poorly soluble pharmaceutical compounds and water-insoluble or poorly soluble drugs.
It is desirable that a water-insoluble or poorly soluble substance be stable when formulated as a dispersion, for example as a dispersion in an aqueous medium such as water. It is also desirable that a formulation of a water-insoluble or poorly soluble substance be stable when formulated as a dispersion. Alternatively, a dry formulation of the substance such as a lyophilized or spray-dried solid form of the formulation can be desirable.
As used herein, xe2x80x9cmicro-xe2x80x9d refers to the largest cross section or diameter such as that of a particle having a cross section or diameter of from nanometers to micrometers. Thus, microparticles, as used herein, refer to solid particles having a cross section or diameter of from nanometers to micrometers and are of irregular or non-spherical or substantially spherical shapes. Drug formulations containing these microparticles provide some specific advantages over unformulated and non-micronized drug particles which include improved oral bioavailability of drugs that are poorly absorbed from GI tract, development of injectable formulations that are currently available only in oral dosage form, less toxic injectable formulations that are currently prepared with organic solvents, sustained release of intramuscular injectable drugs that are currently administered through daily injection or constant infusion, and preparation of inhaled or ophthalmic formulation of drugs that otherwise could not be formulated for nasal/oral inhalation or ocular use.
Current technologies for delivering insoluble drugs as described in U.S. Pat. Nos. 5,091,188; 5,091,187; and 4,725,442 focus either on (a) coating small drug particles with natural or synthetic phospholipids or (b) dissolving the drug in a suitable lipophilic carrier and forming an emulsion stabilized with natural or semisynthetic phospholipids. One of the disadvantages of these formulations is that certain drug particles in suspension tend to grow larger over time because of the dissolution and reprecipitation phenomenon known as xe2x80x9cOstwald ripeningxe2x80x9d or particle growth. As the solvent or medium surrounding the particle becomes saturated with solute such as a drug, the larger particles grow and become even larger as seen, for example in Luckham, Pestic. Sci., (1999) 25, 25-34.
Another approach, as described in a series of patents uses cloud point modifier(s). In U.S. Pat. Nos. 5,298,262; 5,326,552; 5,336,507; 5,304,564 and 5,470,583 a poorly soluble drug or diagnostic agent has adsorbed on its surface both a cloud-point modifier and a non-crosslinked nonionic surfactant. The role of the cloud point modifier is to increase the cloud point of the surfactant such that the resulting nanoparticles are resistant to particle size growth upon heat sterilization at 121xc2x0 C.
U.S. Pat. No. 5,922,355 discloses the preparation of submicron size particles of pharmaceutical or other water-insoluble or poorly water-insoluble substances using a combination of one or more surface modifiers/surfactants such as polaxomers, poloxamines, polyoxyethylene sorbitan fatty acid esters and the like together with natural or synthetic phospholipids. Particles so produced have a volume weighted mean particle size at least one-half smaller than obtainable using a phospholipid alone. Compositions so prepared are resistant to particle size growth on storage. Phospholipid and surface modifier(s) are adsorbed on to the surfaces of drug particles in sufficient quantity to retard drug particle growth, reduce drug average particle size from 5 to 100 micrometers to sub-micron and micron size particles by one or combination of methods known in the art, such as sonication, homogenization, milling, microfluidization, precipitation or recrystallization or precipitation from supercritical fluid, and maintain sub-micron and micron size particles on subsequent storage as suspension or solid dosage form. In U.S. Pat. No. 5,922,355, the second surface modifier may function to suppress Ostwald Ripening, to help maintain particle size, to increase storage stability, to minimize sedimentation, and to decrease the particle growth during lyophilization and reconstitution. The second surface modifier adheres or coats firmly onto the surface of water-insoluble drug particles, and modifies interfaces between the particles and the liquid in the formulations. It increases the interface compatibility between water-insoluble drug particles and the liquid, and it may possibly orient preferentially with hydrophilic portions projected into aqueous medium and with lipophilic portions strongly adsorbed at the water-insoluble drug particle surfaces.
In U.S. Pat. No. 5,922,355, the use of a surface modifier or combination of surface modifiers in addition to a phospholipid provides (i) volume weighted mean particle size values that are at least 50% and preferably about 50-90% smaller than what can be achieved using phospholipid alone without the use of a surfactant with the same energy input, and (ii) compositions resistant to particle size growth on storage.
The present invention focuses on submicron to micron size particles or microparticles coated with a natural phospholipid which particles are prepared using a combination of electrostatic and steric stabilization from at least one charged surface modifier and at least one block copolymer respectively. The growth in size of the particles, and hence their storage stability, is controlled by a combination of electrostatic and steric stabilizing materials.
In particular, this invention describes a pharmaceutical composition comprising electrostatic and steric-stabilized particles having diameters of about 0.05 to about 10 microns of a water-insoluble or poorly soluble drug, said particles having phospholipid coated surfaces and being stabilized with a combination of a charged surface modifier and a block copolymer, wherein the diameter of said particles is greater than about 50% but less than 100% of the diameter of particles comprising said poorly soluble drug and said phospholipid coated surfaces prepared by otherwise identical means in the absence of said combination of charged surface modifier and block copolymer, and wherein the charged surface modifier provides electrostatic stabilization and the block copolymer provides steric stabilization that minimize particle size growth caused by Ostwald ripening and particle aggregation and provides for small particle formation.
In addition, this invention describes a pharmaceutical composition comprising electrostatic and steric-stabilized particles having diameters of about 0.05 microns to about 10 microns of a water-insoluble or poorly soluble drug, the particles coated with a mixture of 0.01% to 50% wt naturally occurring phospholipids, 0.01 to 5.0% wt of a charged surface modifier and 0.01 to 20% wt of a block copolymer, wherein the diameter of said particles is greater than about 50% but less than 100% of the diameter of particles comprising said poorly soluble drug and said naturally occurring phospholipids prepared by otherwise identical means in the absence of both said charged surface modifier and said block copolymer, and wherein the charged surface modifier provides electrostatic stabilization and the block copolymer provides steric stabilization (against) that minimize particle size growth caused by Ostwald ripening and particle aggregation and provides for small particle formation.
In addition, this invention also describes a pharmaceutical composition comprising a powder of electrostatic and steric-stabilized particles having diameters of about 0.05 microns to about 10 microns of a water-insoluble or poorly soluble drug, the particles coated with a mixture of 0.01% to 50% wt naturally occurring phospholipids, 0.01 to 5.0% wt of a charged surface modifier and 0.01 to 20% wt of a block copolymer, wherein the diameter of said particles is greater than about 50% but less than 100% of the diameter of particles comprising said poorly soluble drug and said naturally occurring phospholipids prepared by otherwise identical means in the absence of both said charged surface modifier and said block copolymer, and wherein the charged surface modifier provides electrostatic stabilization and the block copolymer provides steric stabilization (against) that minimize particle size growth caused by Ostwald ripening and particle aggregation and provides for small particle formation
Unlike U.S. Pat. No. 5,922,355, the current invention provides particles that do not exhibit a reduction in volume weighted mean particle size values that are at least 50% or smaller than what can be achieved using phospholipid alone without the use of a surfactant with the same energy input. In addition, the current application provides particles whose subsequent growth is minimized by the presence of the combination. These points are exemplified in the tables of data in the examples that follow hereinbelow.
The use of this particular combination of electrostatic and steric stabilizers in addition to a natural phospholipid is characterized by its ability to result in volume weighted mean particle size values that are smaller than what can be achieved using phospholipid alone without the use of a surfactant with the same energy input, and provide compositions resistant to particle size growth on storage. In order to achieve the advantages of the present invention it is necessary that the natural phospholipid and stabilizers all be present at the time of particle size reduction or precipitation.
Another aspect of the present invention includes free-flowing powders of formulations containing these microparticles of poorly soluble or insoluble drug substances such as particles of cyclosporin as well as solid dosage forms of these powders, for instance in the form of compressed tablets and the like. Surprisingly we have found that microparticle formulations exhibit enhanced stability as illustrated in the data that follows.
Although we do not wish to be bound by any particular theory, it appears that these surface modifiers generally, that is phospholipids and one or more charged surface modifiers and block copolymers, these both sometimes referred to herein as surface modifiers or surfactants, adsorb to the surfaces of drug particles, and (a) convert lipophilic to hydrophilic surfaces with increased steric hindrance/stability, and (b) possibly modify zeta potential of surfaces with more charge repulsion stabilization. The concentrations of surface modifiers used in the process described here are normally above their critical micelle concentrations (CMC). Hence the formation of sub-micron to micron size particles is facilitated by stabilization of the small particles as they are formed to prevent reaggregation.
Phospholipid and surface modifier(s) are adsorbed onto the surfaces of drug particles in sufficient quantity to retard drug particle growth, reduce drug particle average size from 5 to 100 xcexc to sub-micron and micron size by one or a combination of methods known in the art, such as sonication, homogenization, milling, microfluidization, precipitation or recrystallization or precipitation from supercritical fluid, and maintain sub-micron and micron size on subsequent storage as a suspension of particles or as a solid dosage form.
The formulations of particles prepared by this invention may be dried into powders, e.g., by lyophilization, fluid or spray drying, which powders can be resuspended or filled into capsules or converted into granules or tablets with the addition of binders and other excipients known in the art of tablet making.
By industrially useful insoluble or poorly soluble compounds we include biologically useful compounds, imaging agents, pharmaceutically useful compounds and in particular drugs for human and veterinary medicine. Water insoluble compounds are those having a poor solubility in water, that is less than 5 mg/ml at or near neutral pH of 5 to 8, although the water solubility may be less than 1 mg/ml and even less than 0.1 mg/ml.
Examples of some preferred water-insoluble drugs include immunosuppressive agents such as cyclosporins including cyclosporine (cyclosporin A), immunoactive agents, antiviral and antifungal agents, antineoplastic agents, analgesic and anti-inflammatory agents, antibiotics, anti-epileptics, anesthetics, hypnotics, sedatives, antipsychotic agents, neuroleptic agents, antidepressants, anxiolytics, anticonvulsant agents, antagonists, neuron blocking agents, anticholinergic and cholinomimetic agents, antimuscarinic and muscarinic agents, antiadrenergic and antiarrhythmics, antihypertensive agents, hormones, and nutrients. A detailed description of these and other suitable drugs may be found in Remington""s Pharmaceutical Sciences, 18th edition, 1990, Mack Publishing Co. Philadelphia, Pa.
The phospholipid may be any naturally occurring phospholipid or mixtures of phospholipids, sometimes referred to herein as xe2x80x9ccommercialxe2x80x9d phospholipids, such as egg or soybean phospholipid or a combination thereof. The phospholipid may be salted or desalted, hydrogenated or partially hydrogenated or natural semisynthetic or synthetic. Examples of commercially available phospholipids include but are not limited to egg phospholipids P123 (Pfanstiehl), Lipoid E80 (Lipoid); and hydrogenated soy phospholipids, Phospholipon 90H, and 100H (Natterman), and 99% pure egg and soy phosphatidyl choline (Avanti Polar Lipids). The amount of phospholipid present in the composition ranges from 0.01% to 50%, preferably from 0.05% to 20%.
Block copolymers used in the invention display a brush-like interfacial conformation and possible steric stabilization to the particles. Suitable block copolymers include polaxomers, such as Pluronic(trademark) F68, F108 and F127, which are block copolymers of ethylene oxide and propylene oxide available from BASF; and poloxamines, such as Tetronic(trademark) 908 (T908, T707, T909, T1107 and T1307), which are tetrafunctional block copolymers derived from sequential addition of ethylene oxide and propylene oxide to ethylene-diamine available from BASF; TritonTM(trademark) X200, which is an alkyl aryl polyether sulfonate, available from Rohm and Haas. In a preferred aspect of the invention, when free-flowing formulations are desired, the block copolymer will itself be a powder. The amount of block copolymer is between 0.01% and 20%, preferably from 0.1% to 10%.
The charged surface modifier(s) used in the present invention are highly purified phospholipids either isolated from natural products or prepared synthetically. For example, commercially available phosphatidylcholine contains a small percentage of charged phosphalides such as phosphatidyl glycerol, phosphatidyl inosite, phosphatidyl serine and phosphatidic acid and its salts. Other charged phospholipids include palmitoyl-oleyl-phosphatidyl-glycerol (POPG) and dimiristoyl phosphatidylglycerol sodium salt (DMPG). Combinations of charged phospholipids may be used. These materials are present in relatively small amounts and serve to allow smaller particle formation and inhibit aggregation. The amount of charged phospholipids ranges from 0.01% to 5.0% and preferably from 0.05% to 1.0%.
It is thought that some of the functions of the combination of surface modifiers in this invention are (a) to suppress the process of Ostwald Ripening and thereby maintain the particle size, (b) to increase the storage stability, minimize agglomeration and sedimentation, and decrease the particle growth during lyophilization and reconstitution; (c) to adhere or coat onto the surfaces of water-insoluble drug particles and thereby modify the interfaces between the particles and the liquid in resulting formulations; (d) to increase the interface compatibility between water-insoluble drug particles and the liquid; and (e) possibly to orienting themselves preferentially with their hydrophilic portion directed or protruding into the aqueous solution and their lipophilic portion strongly adsorbed at the water-insoluble drug particle surfaces; and (f) to prevent aggregation of the small particles into clumps or aggregates as they are being formed using size reducing equipment or precipitation, such aggregates appearing in particle size measurement apparatus outputs as larger particles.
Considerable variations in the identities and types of charged surface modifier and especially the block copolymer are expected. The variations are anticipated to depend on the physical and chemical properties of the drug or active agent selected because the surface properties of small particles of different drugs are likely to be different. The most advantageous agents for an insoluble drug will be apparent as a result of empirical tests that can identify the phospholipid/charged surfactant/steric stabilizer system or combination that will provide initially desired microparticle size and microparticle size stability on storage over time. Such tests can include solubility and chemical compatibility evaluations, factorial design experiments, preliminary small scale formulation preparations, particle size analysis, pH analysis, temperature profiling, phase compatibility analysis, calorimetry, thermal analysis, spectroscopic analysis, Xray diffration analysis, short and long term stability evaluation, optical analysis, microscopic analysis, and other tests.
Various procedures can be used to produce these stable sub-micron and micron size microparticles. An example of such a procedure comprises the steps of mixing or premixing an insoluble substance such as a drug with phospholipid, charged surface modifier or stabilizer, and block copolymer or steric stabilizer followed by a particle size reduction step employing energy input such as sonication, milling, homogenization, microfluidization, and the like. Another example comprises the precipitation of a water insoluble or poorly water soluble substance from a solution using antisolvent in the presence of phospholipid, charged surface modifier or stabilizer, and block copolymer or steric stabilizer. Precipitation of drug from solvent can be done in the presence of the phospholipid and surfactant(s). Mannitol, other disaccharides, and other agents and excipients may be added to adjust the final formulation to isotonicity. Formulation stabilizing aids such as sugars can be added to stabilize the dispersions of microparticles during drying, for example during lyophilization or spray drying.
Unless otherwise specified, all parts and percentages reported herein are weight per unit volume (w/w), in which the volume in the denominator represents the total volume weight of the system. Diameters of dimensions are given in millimeters (mm=10xe2x88x923 meters), micrometers (xcexcm=10xe2x88x926 meters), nanometers (nm=10xe2x88x929 meters) or Angstrom units (=0.1 nm). Volumes are given in liters (L), milliliters (mL=10xe2x88x923 L) and microliters (xcexcL=10xe2x88x926L). Dilutions are by volume. All temperatures are reported in degrees Celsius. The compositions of the invention can comprise, consist essentially of or consist of the materials set forth and the process or method can comprise, consist essentially of or consist of the steps set forth with such materials.